#2022GM/Q09
#2022BSQ-NOV/Q18
#2020BSQ-NOV/Q56

"Paraneoplastic syndromes refer to groupings of symptoms that occur in patients with malignant neoplasms that cannot be readily explained by local invasion or distant metastasis of the tumor, or the elaboration of hormones indigenous to the tissue of origin of the neoplasm. Paraneoplastic syndromes occur in 10–15% of cancer patients."
Definition of paraneoplastic syndromes in Robbin's Basic Pathology:
They can be triggered by an abnormal immune response to the tumour, or by substances secreted by the neoplasm itself.

2. Cushing's syndrome due to ectopic ACTH production
3. non bacterial thrombotic endocarditis caused by hypercoagulability.

   1. The term nonbacterial thrombotic endocarditis (NBTE), or marantic endocarditis, refers to a spectrum of lesions ranging from microscopic aggregates of platelets to large vegetations on previously undamaged heart valves (most often aortic and mitral) in the absence of a bloodstream bacterial infection. Source
      The cancers most commonly associated with paraneoplastic syndromes (PNS) are

• anti-Hu antibody indicates the presence of a small cell lung cancer
• the anti-Yo antibody, the presence of an ovarian or breast cancer. Source

Hypercoagulability
Trousseau syndrome - migratory thrombophlebitis occuring in association with malignancy.
Nephrotic syndrome - commonest cause is membranous nephropathy.
HPO - hypertrophic pulmonary osteoarthropathy (clubbing of fingers and toes)
Inflammatory myopathies - [[2021 General Medicine July#Polymyositis and dermatomyositis|DM and PM]]

Carcinoid tumours :

The most common biologically active substance secreted from carcinoid tumors is 5-HT (serotonin), a vasoactive peptide whose biosynthesis is accomplished nearly exclusively by the enterochromaffin cells. Synthesized from the amino acid tryptophan, the release of 5-HT into the systemic circulation can cause the classic symptoms of the carcinoid syndrome, which include diarrhea, episodic flushing, bronchoconstriction, and eventual right-sided valvular heart disease

ImageSource

[[Hypertension in pregnancy#Paraneoplastic syndromes associated with lung cancer]]

• It is a common ==multisystemic== ==inflammatory== disease that begins more frequently between 20 and 60 years of age and represents the most frequent of all interstitial lung diseases.
  [!TIP] Bilateral Hilar lymphadenopathy SCaLP

• Loss of superficial reflexes
  • Development of extensor plantar response (Babinski).
• Nystagmus

Eosinophilic oesophagitis

Incidence is increasing.
Symptoms:

• Adults -> Dysphagia.
• Children -> GORD
  Histologically characterized by eosinophillic infiltration of the oesophagus even distal from the gastro-oesophageal junction.
  Patients have a history of atopy.
  Treatment: dietary avoidance of cow's milk and soy products.
  Topical or systemic steroids.

Barrett oesophagus

#2020BSQ-NOV/Q51

• Oesophageal epithlial metaplasia from squamous to columnar secondary to chronic GORD.
• Commonest in middle aged (40-60) white males.
• If the affected portion is > 3cm long -> "long segment Barrett"
  • If < 3m long -> Short segment Barrett; Long segment has higher risk of cancer.
• BO is associated with increased risk of oesophageal cancer but most patients with BO do not go on to develop oesophageal cancer.
• However, the vast majority of oesophageal cancers are associated with Barett oesophagus.
• Seen as red velvety patches on endoscsopy.
• Goblet cells are seen in the metaplastic mucosa.
• This metaplasia is irreversible
• Superimposed dysplasia (which is a premalignant lesion) develops in a minority.
  -If dysplasia is present, endoscopic surveillance (with biopsy) is done every 6 months untill reversion to nondysplastic Barrett oesophagus.
• Barrett oesophagus is not reversible
• However, as above, the dysplasia can regress.
• H pylori infection actually appears to be protect the oesophagus against acid and Barrett oesophagus because the chronic gastritis reduces acid secretion. Source

Pathology of myocardial infarction

Gross Morphologic features of the heart following MI

[!INFO] Changes after MI: A summary of the changes given in Robbins.

• Upto about 4 hours, it looks like nothing happened.
• Then the infarct slowly mottles and darken upto about 24 hours.
• From then on, coagulative necoris changes are seen.
• Phagocytosis of the coagulative necrotic area starts after about 3 days and continues upto 7 days.
• Laying down of granulation tissue begins around 7 days and intensifies upto 14 days.
• Laid down granulation tissue begins to turn fibrotic by about 14 days (2 weeks).
• Scar formation is complege by 8 weeks, the scar has formed.

• No changes visible until 4 hours.
• From 4 to 24 hours, mottling appears and darkens.
• From 1 - 3 days, infarcted area becomes apparent as a yellow - tan area. (upto 3 days, coagulative necrosis is still occuring)
• From this point onwards, phagocytosis of necrotic cells along with laying down of granulation tissue occurs.
• From 3 to 7 days, the central area softens along with hyperaemia of it's border.
• 7 - 10 days, maximal softening with depressed red-tan margins.
• 10 - 14 days: red gray depressed infarct border.
• Laid down granulation tissue begins to turn fibrotic by about 14 days
• 2 - 8 weeks: Gray white scar, progressive from border towards the center.

Myocardial rupture

• Occurs in 1-5%.
• Commonest in left ventricular free wall: (rupture is commonest in anterior and lateral STEMI). It can be rapidly fatal due to haemopericardium -> tamponade.
• Septal rupture -> VSD and L->R shunt.
• Papillary rupture -> Severe MR.
• Most commonly within 3-7 days after infarction when phagocytosis is maximal and coagulatively necrosed tissues are being removed and replaced by soft granulation tissue.
• Risk factors for rupture:
  • Female gender
  • Age > 60
  • First MI (if previous MIs, the there will be firm fibrotic tissue, protecting against rupture)
  • Absence of hypertrophy.

Fibrosarcoma

#2020BSQ-NOV/Q56

• A cancer of malignant fibroblasts.
• They are cells of mesenchymal origin.
• Non pancreatic mesenchymal tumour are the tumours most commonly associated with hypoglycaemia. Source

Renal tumours

Benign tumours are of no clinical significance as benign cortical papillary adenomas occur in about 40% of adults.

• Oncocytomas are benign tumours of the intercalated cells of the collecting ducts.

Renal cancers are mainly of 3 types

• The commonest are renal cell carcinomas (80%) which arise from the tubular epithelium.
  • Commonest in 50's and 60's. Commoner in males.
  • Smoking, hypertension and obesity and exposure to cadmium are risk factors.
• The second commonest are wilm's tumours (nephroblastoma) which occur in children.
  • the 3rd most common organ cancer in children < 10 years old.
• then primary tumours of the calyces and pelvis.

Symptoms:

• Haematuria (most common)
• flank pain
• Palpable mass.
• Paraneoplastic symptoms:
  • Fever, polycythemia, hypercalcemia, hypertension, Cushing's syndrome, feminization / masculinization.

Neck examination

Symptoms are may be flu like; about 15% develop lymphadenopathy (painless) (usually head and neck) . Symptoms resolve spontaneously in a few weeks to months;

• MRI: multiple ring enhancing lesions. (seeing a single lesion on MRI makes toxoplasmosis unlikely)

Pyrimethamine is an antiparasitic prescription medicine

Congenital toxoplasmosis;

• Choroidoretinitis (may be the only manifestation)
• Macrocephaly, microcephaly, seizures, mental retardation

- Live cysts: Antihelminthing treatment must be combined with steroid which penetrates the BBB (Dexamethasone) to lessen the inflammatory response elicited following death of the parasite. 

Granuloma formation and patterns

A good detailed Source

[!INFO] Exerpt from the summary of the article above:

• Granuloma macrophages can undergo different types of specialized differentiation.
• Multiple additional types of cells can be recruited in the granuloma and influence its structure and function.
• Granulomas can form in response to large and small particles, which can be infectious agents or nonliving objects.
• Many granulomas occur in the context of inflammatory and autoimmune diseases in the absence of a known antigenic trigger.

Granuloma formation is a histologic pattern of chronic inflammation.
The pattern of inflammation can be classified in many ways. (necrotizin or not / Suppurative or not etc.)
This corresponds to the features of the granuloma after 'maturation'.
The prototypes are

• necrotizing - myocobacterial granulomas
  • This occurs when granuloma macrophages undergo necrosis.
  • eg Tuberculous and other infectious granulomas (fungal ones where the pathogen is intracellular). Source
  • Other examples of necrotizing granulomas: rheumatoid nodules and granulomatosis with polyangiitis and occasionally those in sarcoidosis. Source
• non-necrotizing - sarcoidosis.
  • Why these macrophages don't undergo necrosis is non known.
  • Examples: beryllium granulomas, Crohn's granulomas and sarcoidosis.

| Crohn's disease | Occasional non caseating granulomas with dense fibrous infiltrate |

Their membranes begin to interdigitate and the nuclei swell.

Granulomatous diseases

1. Naked granulomas - only sparse lymphocytic infiltrate at margin of granuloma; is a typical sarcoid lesions.

2. Suppurative granulomas - have neutrophils at the center.

   1. Fungal causes
   2. Bacterial causes
   3. Atypical mycobacteria
   4. Pyoderma gangrenosum
   5. Parasitic : leishmaniasis

3. Tuberculoid granuloma - caseous necrosis

   1. Usually in TB. Not in leprosy.

4. Foreign body granulomas

   1. Berylliosis
   2. Silicosis

5. Necrbiotic - contains altered collagen in the center. Also has acellular substances in the center.

   1. Divided into red and blue granulomas depending on the stain colour.
      1. Eosinophils are red.
   • Histology: portal tract infiltrate with hepatic granulomas; changes start in zone 1.

• Clinical features are somewhat distinctive: periporbital oedema, facial oedema, conjunctivitis, fever, splinter haemorrhage, rashes, and peripheral eosinophilia.

Ascariasis

• Soil tranmitted helminths (STHs)
• Aka roundworm
• Transmission is faeco oral by ingestion of fertilized eggs. (unfertilized eggs are not infective).
• Live cycle involves migration through intestine to portal vein to systemic circulation to lung from where they migrate up the trachea -> pharynx and are then swallowed to enter the GIT.
  • One cause of [[2021-SBR-November#Loffler syndrome / Loeffler syndrome|Loeffler syndrome]]
• Adult worms live in the small intestine.
• Adult worms are about 20cm long!
• Symptoms: Usually asymptomatic but very high burden can cause obstruction and perforation.
  • Biliary occulusion
  • Appendicitis
  • Nasopharyngeal expulsion

Treatment:

• Albendazole, mebendazole

• They are Granulomatous diseases
  1. GPA (Granulomatosis with polyangitis) - Wegener's granulomatosis

Lung fibrosis

Drugs causing lung fibrosis

1. Nitrofurantoin
2. Methotrexate
3. Amiodarone
4. Cancer chemotherapy
5. Biologic agents
6. Radiation - Acute pneumonitis - 4 to 12 weeks after therapy, Late - 6 to 12 months after.

[!INFO]
Is pulmonary fibrosis due to drugs dose or time dependant?

Vasculitides / Vasculitis

Classification of vasculitides
Good article on pulmonary vaculitis

#2021SBR-JULQ16

Main groups of vasculitis

1. Primary
   1. Primary idiopathic
      1. Small vessel - ANCA Associated vasculitides - GPA / Wegener's, MPA, EGPA /Churgg Strauss
      2. Medium vessel - PAN, Kawasaki
      3. Large vessel - Giant cell, Takayasu
   2. Primary immune complex mediated - eg. Goodpasture's syndrome (Goodpasture's has less recurrence than GPA - PasTest answers); From the image above, these are small vessel vasculitidies.
      1. Goodpastures's
      2. Henoch-Schonlein purpura
      3. Behcet' disease
      4. IgA nephropathy.
2. Secondary
   1. Secondary to other autoimmune diseases

Large vessel vasculitides

• Involves the aorta and the major tributaries
• They are Granulomatous diseasesi

Polymyalgia rheumatica

Patient it always > 50 years old; sudden onset pain and stiffness (but not weakness) of limb girdles / proximal muscles, associated with raised inflammatory markers.
ALP and gamma GT may be elevated.
Giant cell arteritis is seen in 30% of cases.
Treatment: 15mg prednisilone mane : improvement is significant in 24 to 48 hours.

Giant cell arteritis

#2022SBR Q8
#2021GM-JUL/Q17

[!INFO] The most common idiopathic systemic vasculitis.
Females >>> males (3:1)
Always over 50;
Commonest in scandinavians.

• Inflammatory, granulomatous, arteritis or large cerebral arteries.

• Histology: Cellular infiltrates of CD4+ cells, macrophages and giant cells.

• Patient has usually had past or current PMR. (age always > 50)

• Presentations: Severe headaches, scalp / temple tenderness.

• IX: NCNC anaemia and elevated ESR.

• Treatment should commence immediately.

• Giving steroids is essential, since it can prevent vision loss due to ophthalmic artery ischemia.

• Steroid should be given in much higher doses than PMR.

• High dose steroid therapy can cause osteoporosis.

• Definitive Dx : temporal artery biopsy. Patchy lesions -> >1cm needs to be examined.

• Only half will have [[Miscellaneous respiratory medicine#Polymyalgia rheumatica|polymyalgia rheumatica]]

• Almost never occurs in young people (below 50 years old)

• Liver biochemistry may be abnormal

Takayasu arteritis

Affects the largest vessels in the body: the aorta and it's branches.
Mostly affects women of childbearing age!
AKA pulseless disease or aortic arch syndrome.

[!INFO]
Complete obstruction of the left common carotid

(eg, bruit, especially carotid; blood pressure difference of extremities, difference in pulse volume, claudication, hypertension)
Steroids are the mainstay.
Diagnosis: MR angiograms.
Post prandial abdominal pain, diarrhoea, GI haemorrhage.

Medium vessel vasculitides

• medium and small sized arteries and arterioles (mnemonic: i.e the small arteries which have names).

Polyarteritis nodosa (PAN)

The immune complex mediated medium vessel vasculitis.

[!INFO] Pathology
Segmental, transmural, necrotizing inflammation.
Characteristically, all stages of inflammation are present in different vessels / same vessel.

Robbin williams : As a middle aged man, playing Peter PAN!

1/3 of patients have chronic hepatitis B infection.
Occurs in middle aged men; associated with severe systemic symptoms.
Fibrinoid necrosis of vessel walls -> thrombosis and infarction.
Probably immune complex mediated (as it's sometimes associated Hep B).
Involves ==small arteries within the organs==.
Frequency of involvement : Kidney > heart > liver > GI tract
4. Renal: haematuria and proteinuria.
5. Coronary arteritis causing MI.
6. Liver
7. Bowel ischemia -> acute abdominal pain, necrosis and bleeding
9. Mononeuritis mulitiplex - vaso vasorum infarctions
10. Skin - subcutaneous haemorrhage and gangrene
11. Somehow, lungs aren't involved.

Treatment: Corticosteroids +/- azathioprine.

Kawasaki disease

Predominantly occurs in children < 5 years old.
Systemic medium vessel arteritis. The main problems are due to coronary ischemia caused by coronary artery vasculitis leading to

1. coronary aneurysms
2. thrombosis.

Pathology: transumural inflammation seen but not as severe as PAN.

Treatment:
Steroids to now show benefit!
Single dose of Iv-Ig followed by aspirin.

Small vessel vasculitides

[!TIP] Mnemonic

• small arteries, arterioles, venules and capillaries (mnemonic: the ones which are too small to name)

Small vessel vasculitedes are divided into

1. ANCA-associated vasculitis (AAV) - paucity of vessel wall immunoglobulin and presence of ANCA.
   3. MPA (Microscopic polyangitis) - no other name.

   1. GPA (Granulomatosis with polyangitis) - Wegener's ganulomatosis
   2. EGPA (Eosinophilic granulomatosis with polyangiitis)- Churg Strauss syndrome

2. Immune complex SVV - prominence of vessel wall immunoglobulin.

[!INFO] Features common to small vessels vasculitides
Of vasculitidies, small vessel vasculitides commonly affect the lungs.
Small vessel vasculitides are ANCA positive.
Frequent kidney involvement

mnemonic: G for greenwich ; GPA is in europe.

GPA and MPA

[!INFO] Types of ANCA antibodies
It was found that the serum of patients with vasculitis would stain neutrophils in one of two pattersn:

1. Perinuclear - this serum has p-ANCA antibodies
2. Cytoplasmic - this serum has c-ANCA antibodies.
   C-ANCA stains neutrophil proteinsase 3 (PR3 ANCA = cANCA)
   P-ANCA stains neurtrophil myeloperoxidase (MPO ANCA = pANCA)
   
   c in C3PO and 3 is also in C3PO

pANCA - MPA and EGPA
cANCA - GPA
" c " in c-ANCA looks like " G " in GPA.

should be suspected in any patient who presents with
constitutional symptoms along with
clinical evidence of glomerulonephritis,
upper or lower respiratory tract involvement, or multiple mononeuropathy.

Fortunately for US, MPA and GPA are similar diseases but with some differences.
They present in older adults.

most commonly affected organs are upper and lower respiratory tract and kidneys.

URT - Otitis (even hearing loss), bloody nasal discharge, crusting, oral or nasal ulcers.
LRT - hoarseness, dry cough, pleuritic chest pain, life threatening haemoptysis.
Kidney - rapidly proliferative glomerulonephritis. -> nephritic picture
Skin - purpura of lower extremeties.

GPA and MPA are similar but differ in the following:

GPA

[!TIP] Otitis, sinusitis, cough and glomerulonephritis and an older adult

GPA is the commonest ANCA associated vasculitis.
It is a granulomatous disease. The granulomas are not well formed like those in TB or sarcoidosis.
However, the granulomas can obstruct blood vessels and are necrotizing granulomas.

Lungs: Liquefactive necrosis seen in granulomas.
Kidneys: Focal necrotizing glomerulonephritis with crescents and thrombosis.

Affects older adults.
c-ANCA positive.

Upper respiratory tract : sinusitis , ears -> Otitis media.
Glomerulonephritis is present.

Diffuse alveolar haemorrhage and life threatening haemoptysis occurs in upto 45%.
Cough, dysponoea, pleuritic chest pain.

Staining pattern characteristic of each ANCA type
c-ANCA - diffuse staining
p-ANCA - perinuclear staining

EGPA

Presents in early adulthood.
Eosinophilia+
Allergic rhinitis and asthma that's difficult to control.
p-ANCA positive. (=MPO ANCA)

Systemic vasculitis develops later:

1. Tender subcutaneous nodules
2. Mononeuritis multiplex
3. heart
4. Kidneys

Responds well to steroids.